rs1364039811

Variant names:

• chr6-123381381-G-A
• rs1364039811
• NM_006073.4:c.1175C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-123381381-G-A
• chr6-123381381-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006073.4(TRDN):​c.1175C>T​(p.Pro392Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,405,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.772
• Publications: 0 publications found

Genes affected

TRDN (HGNC:12261): (triadin) This gene encodes an integral membrane protein found in skeletal and cardiac muscle. The encoded protein plays a role in skeletal muscle excitation-contraction coupling as part of the calcium release complex and is required for normal skeletal muscle strength. This protein indirectly links triads and microtubules in skeletal muscle. Mutations in this gene are associated with cardiac arrythmia syndrome and some variants in this gene may be associated with sudden cardiac death. [provided by RefSeq, May 2022]

TRDN Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• familial long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06803924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1175C>T	p.Pro392Leu	missense_variant	Exon 16 of 41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.1178C>T	p.Pro393Leu	missense_variant	Exon 16 of 21		NP_001238916.1
TRDN	NM_001407315.1	c.1118C>T	p.Pro373Leu	missense_variant	Exon 15 of 20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1175C>T	p.Pro392Leu	missense_variant	Exon 16 of 41	1	NM_006073.4	ENSP00000333984.5
TRDN	ENST00000662930.1	c.1178C>T	p.Pro393Leu	missense_variant	Exon 16 of 21			ENSP00000499585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1405434 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 694128

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32216

American (AMR) AF: 0.00 AC: 0 AN: 36970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 37038

South Asian (SAS) AF: 0.00 AC: 0 AN: 79556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1081598

Other (OTH) AF: 0.00 AC: 0 AN: 58270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Aug 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with leucine at codon 392 of the TRDN protein (p.Pro392Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with TRDN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Catecholaminergic polymorphic ventricular tachycardia 5 Uncertain:1

Oct 01, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.77
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.040
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.031	D
Polyphen		0.0050	B
Vest4		0.15
MutPred		0.23		Loss of loop (P = 0.0128);
MVP		0.12
ClinPred		0.15	T
GERP RS		0.96
Varity_R		0.074
gMVP		0.0064
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1364039811; hg19: chr6-123702526;